RNA Biology and Innate Immune Sensing

The RNA Biology and Innate Immune Sensing Research group investigate how RNA regulation influences both normal development and disease. By uncovering these mechanisms, they aim to advance the understanding of cellular processes and identify new strategies for inflammatory disease, rare inherited disorders and cancer.

Overview

RNA (ribonucleic acid) is a molecule essential for various biological roles, including coding, decoding, regulation, and expression of genes. RNA plays a key role in translating genetic information from DNA into proteins, as well as in various regulatory and catalytic functions within the cell.

The RNA Biology and Innate Immune Sensing Research group, under the guidance of Professor Carl Walkley, investigates how RNA modification by the family of Adenosine Deaminase Acting on RNA (ADAR ) proteins, called ADAR1 and ADAR2, alter the RNA landscape, influencing normal biological processes and disease development. They are particularly interested in the normal roles of ADAR1 and the consequences of its editing of cellular RNAs. They seek to understand

The cellular and organismal consequences of A-to-I editing
The protein or gene networks that a cell can use to regulate the response to unedited cellular dsRNA,
How these two processes intersect with pathologies associated with changes in ADAR1 function or editing including in cancer, infection and autoinflammatory conditions. This is relevant to understanding how mutations in ADAR1 cause human disease, such as the rare childhood disease Aicardi-Goutières Syndrome.

The team are also interested in understanding rare human disease syndromes, particularly those related to an increased risk of cancer. In this line of study, they are focused on Rothmund-Thomson Syndrome and how the gene identified in this disease, RECQL4, functions. They generate models to identify how the key genes involved in these syndromes function, and to use them to identify and test potential new therapeutic options for these diseases.

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Areas of focus

Understanding how RNA modifications, particularly A-to-I RNA editing by ADAR1, influence normal biology and disease development.
Generating and using models of human cancers, such as bone cancer and osteosarcoma, to understand how they develop and, using this information, find better treatments.

Research Group Head | Professor Carl Walkley

I study how RNA is regulated and modified in the human body to maintain health, and what happens when RNA becomes dysregulated, potentially leading to uncontrolled cell growth and cancer. My goal is to uncover new insights into these disease mechanisms, which could lead to new therapeutic strategies and improved patient outcomes.

Meet the team

News from the lab

Student opportunities

Collaborators

Publication highlights

Hu S*, Heraud-Farlow JE*, Sun T, Liang Z, Goradia A, Taylor S, Walkley CR*, Li JB* (2023) ADAR1p150 Prevents MDA5 and PKR Activation via Independent Mechanisms to Protect against Fatal Autoinflammation. Molecular Cell 83(21):3869-3887.E7.
Mendez Ruiz S, Chalk AM, Goradia A, Heraud-Farlow JE*, Walkley CR* (2023) Over-expression of ADAR1 in mice does not initiate or accelerate cancer formation in vivo. Nucleic Acid Research Cancer 5(2):zcad023.
Liang Z, Chalk AM, Taylor S, Goradia A, Heraud-Farlow JE*, Walkley CR* (2023) The phenotype of the most common human ADAR1p150 Za mutation P193A in mice is partially penetrant. EMBO Reports 24(5):e55835.
Xu JJ, Chalk AM, Wall M, Langdon WY, Smeets MF*, Walkley CR* (2022) Srsf2^P95H/+co-operates with loss of TET2 to promote myeloid bias and initiate a chronic myelomonocytic leukemia-like disease in mice. Leukemia 36(12):2883-2893.
Chalk AC, Taylor S, Heraud-Farlow JE*, Walkley CR* (2019) The majority of A-to-I RNA editing is not required for mammalian homeostasis. Genome Biology 20:268.
Smeets MF, Tan SY, Xu JJ, Anande G, Unnikrishnan A, Chalk AM, Taylor SR, Pimanda JE, Wall M, Purton LE, Walkley CR (2018) Srsf2^P95H initiates myeloid bias and myelodysplastic/myeloproliferative syndrome (MDS/MPN) from hemopoietic stem cells. Blood 132(6):608-621
Tan MH, Li Q, Shanmugam R, Piskol R, Kohler J, Young AN, Liu KI, Zhang R, Ramaswami G, Ariyoshi K, Gupte A, Keegan LP, George CX, Ramu A, Huang N, Pollina EA, Leeman DS, Rustighi A, Goh YPS, GTEx Consortium, Chawla A, Del Sal G, Peltz G, Brunet A, Conrad DF, Samuel CE, O’Connell MA, Walkley CR, Nishikura K, Li JB (2017) Dynamic landscape and regulation of RNA editing in mammals. Nature 550:249-254.
Tan MH, Li Q, Shanmugam R, Piskol R, Kohler J, Young AN, Liu KI, Zhang R, Ramaswami G, Ariyoshi K, Gupte A, Keegan LP, George CX, Ramu A, Huang N, Pollina EA, Leeman DS, Rustighi A, Goh YPS, GTEx Consortium, Chawla A, Del Sal G, Peltz G, Brunet A, Conrad DF, Samuel CE, O’Connell MA, Walkley CR, Nishikura K, Li JB (2017) Dynamic landscape and regulation of RNA editing in mammals. Nature 550:249-254.
Liddicoat BJ, Piskol R, Chalk AM, Ramaswami G, Higuchi M, Hartner JC, Li JB, Seeburg PH, Walkley CR (2015) RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as non-self. Science 349(6252):1115-20.
Hartner JC, CR Walkley, J Lu & SH Orkin (2009) ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. Nature Immunology 10(1):109-115.
Walkley CR, JM Shea, NA Sims, LE Purton & SH Orkin (2007) Rb Regulates Interactions Between Hematopoietic Stem Cells and their Bone Marrow Microenvironment. Cell 129: 1081-1095.
Walkley CR*, G. Haines Olsen*, S Dworkin, SA Fabb, J Swann, GA McArthur, SV Westmoreland, P Chambon, DT Scadden & LE Purton (2007) A Microenvironment-Induced Myeloproliferative Syndrome Caused by Retinoic Acid Receptor γ Deficiency. Cell 129: 1097-1110.

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